Ferroptotic death is the penalty for losing control over three processes—iron metabolism, lipid peroxidation and thiol regulation—that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NO•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells, whereas NO• donors empower resistance of M2 cells to ferroptosis. In vivo, M1 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (ETE)-PE intermediates and oxidatively truncated species by NO• donors and/or suppression of NO• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.
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The raw data are available at the following link https://data.mendeley.com/datasets/t4jyhhf3gw/draft?a=76c6ac56-4305-463e-bebc-b004c2000edb.
Code used for the analysis of the MD simulations of NO• interactions with 15-LOX has been made available in two formats: (1) Jupyter Notebook and (2) html (https://onedrive.live.com/?authkey=%21AFEVmP5sOP1km0s&id=4960CA1B5C7F3FD%219568&cid=04960CA1B5C7F3FD).
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This work was supported by NIH (HL114453-06, U19AI068021, CA165065-06, NS076511, NS061817, P41GM103712) and by Russian academic excellence project ‘5-100’.
The authors declare no competing interests.
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Kapralov, A.A., Yang, Q., Dar, H.H. et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 16, 278–290 (2020). https://doi.org/10.1038/s41589-019-0462-8
Biochemical Pharmacology (2020)